3, 17-bisoxygenated 16-haloestrenes and intermediate



United States "3,17-'BISOXYGENATED ld-HALOESTRENES AND INTERMEDIATEWilliam F. John's, Morton Grove, 111., assignor a) G. u.

Seal-1e & C01, Chicago, 111., a corporation of Delaware No Drawing.Filed May 18, 19 59,Ser. No. 813,671 '6 Claims. 01. zen-4,913

The present invention relates to l6 -halogenated steroids which containa monounsaturated A ring and to an intermediate in the manufacture ofsame. The compounds especially contemplated are 3,17-bisoxygenated 16-halo-- est'renes of the structural formulae and atent O' ce 2,949,471?Patented Aug. 16, 1960 medium, the 16a-halo-3fl,17-diols of thisinvention result. For instance, 3fl-acetoxy-l6a-chloroestr5(10)-en-17-onetetrahydrofuran is reacted with lithium aluminum hydride in etherto yield 16a-chloroestr-5(10)-en- 3 8,17-diol. Selective oxidation ofthese diols, typically by treatment with a limited quantity of chromiumtrioxide in aqueous sulfuric acid, results in the instant16ahalo-17-hydr'oxyestr-5(10)-en-3-ones; whereas reaction of the diolswith a lower alkanoic acid anhydride in pyridine yields thecorresponding 313,17-di-(lower alkanoates).

By methods which are Well-known to those persons skilled in the art, the165-isomers of the aforementioned 160L-hfl10 compounds can bemanufactured. For instance,

A starting material suitable for the manufacture of the l compounds ofthis invention is estr 5 (10)-ene-3,17-dione. Reduction of thisdiketone, typically with sodium borohydride' in aqueous methanol,-results in SB-hydroxy-estr- 5(l'O)-en-17-one which can be converted tothe enol acetate, 3B,17-diacetoxyestra-5(10),16-diene, by treatment withisopropenyl acetate in the presence of a catalytic quantity ofp-toluenesulfonic acid. This enol acetate is transformed into aloot-halogenated 17-ketone of this invention by reaction with theappropriate halogen in a suitable inert solvent. As a specific exampleof the process involved, 3 8,l7-diacetoxyestra-5(10),l6-diene is reactedwith chlorine in carbon tetrachloride to aiford 3B-acetoxy-l6a-chloroestr-5 (10)-'en-17-one. These 3B-(lower alkanoates)are hydrolyzed,- typically in methanol with aqueous hydrochloric acid,to afford the corresponding 16d-halo-3B hydroxyestr-5(10)-en-l7-ones.

The instant 16 t=halo-3,1 7-diones can be prepared by oxidation of theaforementioned 3fi-hydrox-y derivatives. For example,16a-chloro-3,6-hydroxyestr-5 (10)-'en-l7- one isreacted with a solutionof chromium trioxide in aqueous sulfuric acid to afford16a-chloroestr-5(10)-ene- 3;1 7 dione. On the other hand, when the16a-ha1o-3 6- hydr'oxyestr -5 10) e"n-17 -ones or their SIB-(loweralkanoates) are treated-with a reducing agent in a suitable thelofl-chloro and 16fl-bromo isomers are prepared by treating thecorresponding l6oc-i0d0 compounds of this invention with the appropriatelithium halide. The 165- iodo isomers, however, are preferably preparedby way of the aforementioned enol acetate, 35,17-diacetoxyestra-5(10),16-diene. Treatment of the latter compound with N-iodosuccinimidein a suitable inert solvent such as dioxane yields 3,8 acetoxy 16piodoestr-S (10*)-en-17-one which can be converted, as is specifiedsupra, to the other IGfl-iodo compounds of this invention.

The instant 16-haloestr-4-ene-3,17-diones can be prepared by Oppenaueroxidation of the aforementioned16-halo-3p-hydr'oxyestr-5(10)-en-17-ones. As a specific example,16a-chloro-3/3-hydroxyestr-5(10)-en-17-one is reacted with aluminumisopropoxide and cyclohexanone iri toluene, to afiord16a-ch1oroestr-4-ene-3,17-dione. As will be evident to those personsskilled in the art, derivatives of the latter dione can be obtained bythe processes described supra.

The 3,6,17-bisoxygenated 16-haloestrenes of this invention are useful asa result of their valuable pharmacological properties. They have, forexample, the capacity to decrease the serum cholesterol/phospholipidratio without at the same time producing the potent feminizing sideeffects characteristic of known estrogens adapted to regulation ofcholesterol metabolism. They have also antihormonal properties asexemplified by their ability to inhibit the salt-retaining eifect ofdesoxycorticosterone acetate. In addition, they are androgenic agents.

The invention Will appear more fully from the ex amples which follow;These examples are set forth by way of illustration only and it will beunderstood that the invention is not tobe construed as limited in spiritor in scope by the details contained therein, as manyv Example 1 To asolution of 165 parts of estr-S 10)-ene-3,17-dione in 3200 parts ofmethanol is added, at 10-15, a solution of 6.2 parts of sodiumborohydride in 150 parts of Water; and the mixture is stirred for 45minutes. The reaction mixture is treated with parts of acetic acid andthe resultingsolution poured into 4000 parts of water. Theresultingprecipitate is collected by filtration, washed with Water,dried, and dissolved in benzene. Adsorption of the benzene solution on1700 parts of silica gel followed by elution with a 10% ethyl acetate-%benzene solution and recrystallization from acetone-petroleum etherafiords 3B-hydroxyestr-5(l0)-en17-one, M.P. 192-194"; [a] =|-27O.

Example 2 A mixture of 53 parts of 3B-hydroxyestr-5(1,0)-en-17- one, 7parts of p-toluenesulfonic acid and 630 parts of isopropenyl acetate isdistilled slowly to approximately half-volume. This operation usuallyrequires about 20 hours. The mixture is cooled and treated with etherand aqueous potassium bicarbonate; and the organic solution separated,washed with equeous potassium bicarbonate,

. dried over anhydrous magnesium sulfate, and concenraJ =+163 Example 3To a stirred mixture of 17.2 parts of35,17-diacetoxyestra-5(10),16-diene, 30 parts of potassium carbonate,and 560 parts of carbon tetrachloride is added, at over a period of 15minutes, a solution of 4.8 parts of chlorine in 200 parts of carbontetrachloride The reaction mixture is treated with excess aqueous sodiumthiosulfate and extracted with chloroform; and the organic extractwashed with water, dried over anhydrous magnesium sulfate, andconcentrated to dryness in vacuo. The residue is triturated with etherthen recrystallized from acetone-petroleum ether to afford pure33-acetoxy-l6ol chloroestr- (10)-en-17-one, M.P. about 208-218".

By substituting an equivalent quantity of bromine or iodine andotherwise proceeding according to the herein described processes,3,3-acetoxy-16a-bromoestr-5 -en- 17-one, M.P. 193-200 and3fl-acetoxy-16a iodoestr-5-- (10)-en-17-one, respectively, are obtained.The latter sub stance displays maxima in the infrared at 5.78 and 8.04microns. Y

Example 4 A mixture of 4.2 parts of 3B-acetoxy-l6a-chloroestr-5(10)-en-17-one, 50 parts of concentrated hydrochloric acid, and 800parts of methanol is stirred at room temperature for about 20 hours. Thereaction mixture is diluted with water and the resulting precipitatecollected by filtration. Recrystallization from acetone-petroleum etheraffords pure 16cc-ChlOIO-3fi'hYGIOXYGStFS(10)-e11- 17-one, M.P. about123-125".

By substituting an equivalent quantity of 3B-acetoxyl6ot-bromoestr-5l0)-en-17-one or 3fl-acetoxy-l6uiodoestr-5(10)-en-17-one and otherwiseproceeding according to the herein described processes,16u-bromo-3/3-hydroxyestr-5(l0)-en-17-one, M.P. 87-90, and3/3-hy'droxy-16ociodoestr-S(10)-en-17-one, respectively, are obtained.

Example 5 To a solution of 18 parts of 16a-chloro-3 8-hydroxyestr-5'(10)-en-17-one in 800 parts of acetone is added dropwise at parts byvolume of an aqueous solution containing 5.34 parts of chromium trioxideand 8.46 parts of concentrated sulfuricacid. The reaction mixture isdiluted with water and extracted with benzene; and the benzene solutionwashed successively with water and aqueous potassium bicarbonate, driedover anhydrous magnesium sulfate, and concentrated to dryness in vacuo.Adsorption of the residue on silica gel followed by elution of thechromatographic column with 1% ethyl acetate in benzene andrecrystallization from acetone-petroleum ether yields16u-chloroesu-5(10)-ener3, 17-dione, M.P. about 153-158.

By substituting an equivalent quantity of 3,B-hydroxy-16a-iodoestr-5(10)-en-l7-one and otherwise proceeding according to theherein described processes, 16a-iodoestr- 5(10)-ene-3,17-dione isobtained.

Example 6 To a stirred mixture of 2 parts of lithum aluminum hydride and600 parts of other is added drop-Wise a solu- 1718hydroxyestr-S(10)-en-3-one.

tion of 3.3 parts of Sfi-acetoxy 16a-chloroestr-5(10)-en- 17-one in 70parts of tetrahydrofuran. Stirring is continued for about 10 minutes,then the mixture treated successively with water and dilute hydrochloricacid. The resulting mixture is extracted with ether and the etherextract washed successively with water and aqueous potassiumbicarbonate, dried over anhydrous magnesium sulfate, and concentrated todryness in vacuo to afford 16a-ch1orestr-5 (10)-ene-3;8,17-diol. Thismaterial can be separated into its two stereoisomerschromatographically. Adsoprtion on silica gel and elution with 5% ethylacetate in benzene followed by recrystallization from acetone-petroleumether affords pure 16achloroestr-S (10)-cne-3;3,l7a-diol, M.P. l78180Further elution of the column with 5% ethyl acetate in benzene andrecrystallization from acetone-petroleum ether results inl6u-chloroestr-5(10)-ene-3fi,17B-diol, M.P 193-196"; [oc] =+l45.

When an equivalent quantity of 3B-acetoxy-16u-iodoestr-5(10)-en-17-oneis substituted in the process disclosed herein, the resulting product is16a-iodoestr- 5(10)-ene-3fi,17-diol.

I Example 7 To a solution of 3.1 parts of 16x-chloroestr-5(10)-ene-3,8,l7 8-diol in 25 parts of acetone is added dropwise at 5, 2.5 partsby volume of an aqueous solution containing 0.67 part of chromiumtrioxideand 1.06 pants of concentrated sulfuric acid. The solution isdiluted with water and extracted with benzene; and the benzene extractwashed successively with water-and aqueous potassium bicarbonate, driedover anhydrous magnesium sulfate, and concentrated todryness in vacuo.Adsorption of the residue on magnesiated silica followed by elution with5% ethyl acetate in benzene and recrystallization from acetone-petroleumether affords l6a-chloro- This substance eX- hibits maxima in theinfrared at 2.84 and 5.82 microns.

By substituting 16a-chloroestr-5(l0)-ene-3,8,17ol-diol or l6a-iodoestr-5(10)-ene-3;3,17-dio1 and otherwise proceeding according to the hereindescribed processes, 16achloro-l7m-hydroxyestr-5 (10)-en-3-one, andl7-hydroxy- 16a-iodoestr-5(10)-en-3-one, respectively, are obtained. Theformer hydroxy ketone exhibits infrared maxima at 2.81 and 5.82 microns.

313,17B-diol, SO parts of acetic anhydride, and parts of pyridine isheated on the steam bath for 15 minutes, then allowed to stand at roomtemperature for 16 hours. Dilution of the mixture with water results ina precipitate which is collected by filtration and dried to aflford3B,1713-diacetoxy-16ol-chloroestr-5(10)-ene. The product can berecrystallized from aqueous ethanol to yield the pure substance, whichexhibits maxima in the infrared at 5.79 and 8.04 microns.

By substituting isovaleric anhydride and otherwise proceeding accordingto the herein described processes, 16a chloro 35,173diisovaleryloxyestr- 5 (10) ene is obtained. This compound possessesmaxima in the infrared at 5 .79 and 8.05 microns.

Example. 9

, filtration and dried to yield3fi-n-butyroxy-16u-ch1oroestr-5(10)-en-17-one. This compound displaysmaxima in the infrared at 5.78 and 8.05 microns.

5 Substitution of an equivalent quantity of 3fi-hydroxy-16a-iodoestr-5(10)-en-17-one in the process described herein results in3B-n-butyroxy-16a-iodoestr-5(10)-en- 17-one.

What is claimed is: 1. A compound of the structural formula wherein X isselected from the group consisting of carbonyl, hydroxymethylene, and(lower alkanoyDoxymethlene radicals; Z is selected from the groupconsisting of carbonyl, B-hydroxymethylene, and [SI-(loweralkanoyl)oxymethylene radicals; and Y is a halogen atom which has anatomic weight greater than 34.

Q IAWN References Cited in the file of this patent UNITED STATES PATENTSArcher June 15, 1954 Mueller Oct. 7, 1958 Mueller Oct. 7, 1958 MuellerOct. 7, 1958 Fried et a1. Oct. 21, 1958

1. A COMPOUND OF THE STRUCTURAL FORMULA